Indane or dihydroindole derivatives

ABSTRACT

The present invention relates to substituted indane or dihydroindole compounds of  
                 
 
     Formula (I),  
     wherein A and B are independently O or S; D is an optionally substituted methylene group; X is N or optionally substituted C; and W is a spacer group. The compounds are either selective dopamine D4 ligands or they have combined effects at dopamine D4 and serotonergic receptors and/or the serotonergic transporter. These compounds are therefore useful in the treatment of certain psychiatric and neurologic disorders, including psychosis, depression and anxiety.

FIELD OF THE INVENTION

[0001] The present invention relates to a novel class of substitutedindane or dihydroindole compounds having effects at dopamine D₄receptors. The compounds are either selective dopamine D₄ ligands orthey have combined effects at dopamine D₄ and serotonergic receptorsand/or the serotonergic transporter. These compounds are thereforeuseful in the treatment of certain psychiatric and neurologic disorders,including psychosis, depression and anxiety.

BACKGROUND OF THE INVENTION

[0002] Related compounds are known from WO patents Nos. WO 9421627-A1,WO 9421630-A1, WO 94 21626-A1 describing various series of indolyl- orindazolylmethyl piperidine or piperazine derivatives as selectivedopamine D₄ antagonists. No data are given. The compounds are only saidto give K_(i) values of less than 1.5 μM in a test for displacement of3H spiperone from human dopamine D₄ receptor subtypes in clonal celllines.

[0003] EP patent No. 574313 A1 describes compounds with piperidine,tetrahydropyridine, or piperazine rings substituted in position 1 and 4with various aryl or heteroaryl groups, including certain 1-(indane orindanemethyl)piperidine, tetrahydropyridine, or piperazine derivatessubstituted in the 4-position with 1,4-benzodioxane. The compounds areclaimed to have effects at dopamine D₂ and D₄ receptors.

[0004] Dopamine D₄ receptors belong to the dopamine D₂ receptor familyconsidered to be responsible for antipsychotic effects of neuroleptics.Furthermore, dopamine D₄ receptors are primarily located in areas of thebrain other than striatum (Van Tol, et al. Nature, 1991, 350, 610), thelow level in striatum suggesting lack of extrapyramidal activity. Also,dopamine D₄ receptor levels have been reported to be elevated inschizophrenic patients (Seeman et al., Nature, 1993, 365, 441.) and theantipsychotic clozapine which is lacking extrapyramidal side effects,has a high affinity for dopamine D₄ receptors (Van Tol, et al. Nature,1991, 350, 610.)

[0005] Various effects are known with respect to compounds which areligands at the different serotonin receptor subtypes. As regards the5-HT_(2A) receptor which was previously referred to as the 5-HT₂receptor, the following effects have e.g. been reported:

[0006] Antidepressive effect, improvement of the sleep quality (Meert,T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) and thenegative symptoms of schizophrenia and reduction of extrapyramidalside-effects caused by treatment with classical neuroleptics inschizophrenic patients (Gelders, Y. G., British J. Psychiatry, 1989, 155(suppl. 5, 33). Finally, selective 5-HT_(2A) antagonists could beeffective in the prophylaxis and treatment of migraine (Scrip Report;“Migraine—Current trends in research and treatment”; PJB PublicationsLtd.; May 1991).

[0007] Clinical studies have shown that 5-HT_(1A) partial agonists areuseful in the treatment of anxiety disorders such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder (Glitz, D.A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate thatalso full agonists are useful in the treatment of the above mentionedanxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6,S53).

[0008] There is also evidence, both clinical and preclinical, in supportof the beneficial effect of 5-HT_(1A) partial agonists in the treatmentof depression, impulse control disorders and alcohol abuse (van Hest,Psychopharmacol., 1992, 107, 474; Schipper et al, HumanPsychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158,53; Glitz and Poh, Drugs 1991, 41, 11; Grof et al., Int. Clin.Psychopharmacol. 1993, 8, 167-172; Ansseau et al., HumanPsychopharmacol. 1993, 8, 279-283).

[0009] 5-HT_(1A) agonists and partial agonists inhibit isolation-inducedaggression in male mice indicating that these compounds are useful inthe treatment of aggression (Sanchéz et al., Psychopharmacology, 1993,110, 53-59).

[0010] Furthermore, 5-HT_(1A) ligands have been reported to showantipsychotic effect in animal models (Wadenberg and Ahlenius, J.Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol.&Toxicol., 1989, 64,3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med.Chem., 1989, 32, 1147;and Martin et al., J. Med. Chem., 1989, 32, 1052).

[0011] Recent studies also indicate that 5-HT_(1A) receptors areimportant in the serotonergic modulation of haloperidol-inducedcatalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al.Pharmacol.Biochem. & Behav. 1994, 47, 509-513) suggesting that 5-HT_(1A)agonists are useful in the treatment of EPS induced by conventionalantipsychotic agents such as haloperidol.

[0012] 5-HT_(1A) agonists have shown neuroprotective properties inrodent models of focal and global cerebral ischaemia and may, therefore,be useful in the treatment of ischaemic disease states (Prehn, Eur. J.Pharm. 1991, 203, 213).

[0013] Pharmacological studies have been presented indicating that5-HT_(1A) antagonists are useful in the treatment of senile dementia(Bowen et al, Trends Neur. Sci. 1992, 15, 84).

[0014] 5-HT reuptake inhibitors are well known antidepressant drugs.

[0015] Accordingly, dopamine D₄ receptor ligands are potential drugs forthe treatment of psychosis and positive symptoms of schizophrenia andcompounds with combined effects at dopamine D₄ and serotonergicreceptors may have the further benefit of improved effects on otherpsychiatric symptoms in schizophrenic patients such as depressive andanxiety symptoms. As 5-HT_(1A) and 5-HT_(2A) receptor ligand classes ofcompounds and 5-HT reuptake inhibitors have different activities indifferent animal models predictive of anxiolytic and antiaggressiveeffects (Perregaard et al., Recent Developments in Anxiolytics. CurrentOpinion in Therapeutic Patents 1993, 1, 101-128) and/or in modelspredictive of effects in other psychic disorders it might also be highlybeneficial to have such combined serotonergic effects.

SUMMARY OF THE INVENTION

[0016] The object of the invention is to provide compounds with dopamineD₄ activities or with combined effects at dopamine D₄ receptors andserotonergic receptors and/or the serotonergic transporter.

[0017] It has now been found that certain substituted indane ordihydroindole compounds have effects at dopamine D₄ receptors.Additionally, many of the compounds interact with central serotonergicreceptors, in particular with the 5-HT_(1A) and/or the 5-HT_(2A)receptors and/or they act as 5-HT reuptake inhibitors.

[0018] Accordingly, the present invention relates to novel compounds ofthe formula I.

[0019] wherein A and B are independently O or S;

[0020] D is a methylene group optionally substituted with one or twoC₁₋₄ alkyl groups;

[0021] Y is a hydrocarbon group completing an indane ring, a group NR¹completing a dihydroindole ring, or a group N completing a dihydroindolering attached via the 1-position;

[0022] W is a bond, and n+m is 1, 2, 3, 4, 5, or 6;

[0023] W is CO, SO, or SO₂, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3,provided that n+m is not more than 6; or

[0024] W is O, S, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, providedthat n+m is not more than 6, and

[0025] provided that when Y is N completing a dihydroindole ringattached via the 1-position then m is 2, or 3; and when Y is NR¹completing a dihydroindole ring linked via the 2-position then m is 1,2, or 3;

[0026] the dotted line, emanating from X, indicates an optional bond;when it does not indicate a bond X is N, CH or COH; and when itindicates a bond X is C;

[0027] R¹ is selected from

[0028] hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl, heteroaryl,aryl- C₁₋₆ alkyl, heteroaryl-C₁₋₆ alkyl, acyl, thioacyl, C₁₋₆alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl orheteroarylsulfonyl, or

[0029] R¹⁵VCO— wherein V is O or S and R¹⁵ is C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl, or

[0030] a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— wherein R¹⁶ and R¹⁷ areindependently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl, or R¹⁶ and R¹⁷ together withthe N-atom to which they are linked, form a pyrrolidinyl, piperidinyl orperhydroazepin group;

[0031] R²-R⁵ are independently selected from hydrogen, halogen, cyano,nitro, C₁₋₆ alk(en/yn)yl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxy, C₃₋₈cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, C₁₋₆alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl, trifluoromethylsulfonyloxy and C₁₋₆ alkylsulfonyl, oneof R²-R⁵ alternatively being a group —NR¹³R¹⁴ wherein R¹³ is selectedfrom the R¹ substituents;

[0032] R¹⁴ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl, heteroaryl,aryl-C₁₋₆ alkyl or heteroaryl-C₁₋₆ alkyl, or R¹³ and R¹⁴ together withthe N-atom to which they are linked form a group

[0033] wherein Q is C═O, C═S or CH₂; T is NH, S, O or CH₂; and p is 1-4,inclusive;

[0034] or two adjacent groups taken from R²- R⁵ may be joined anddesignate a —(CH₂)₃— or —CH═CH—NH— thereby forming a fused 5-memberedring;

[0035] R⁶-R⁸ are independently hydrogen, halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, or C₁₋₆ alkylsulfonyl;

[0036] with the proviso that the substituent R³ or R⁴ in 6-position maynot be —NR¹³R¹⁴ when Y is CH₂ and the ring is linked via the 1-position;

[0037] and pharmaceutically acceptable acid addition salts thereof.

[0038] The compounds of the invention have been found to show highaffinity for dopamine D₄ receptors and some of the compounds were foundalso to show affinity for serotonergic receptors including 5-HT_(1A)receptors and/or for 5-HT_(2A) receptors. In addition to the effects atthese receptor subtypes, certain of the present compounds also show 5-HTreuptake inhibiting effect.

[0039] Accordingly, the compounds of the invention are considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,alcohol abuse, impulse control disorders, aggression, side effectsinduced by conventional antipsychotic agents, ischaemic disease states,migraine, senile dementia and cardiovascular disorders and in theimprovement of sleep.

[0040] In another aspect the invention provides a pharmaceuticalcomposition comprising at least one compound of Formula I as definedabove or a pharmaceutically acceptable acid addition salt thereof orprodrug thereof in a therapeutically effective amount and in combinationwith one or more pharmaceutically acceptable carriers or diluents.

[0041] In a further aspect the present invention provides the use of acompound of Formula I as defined above or an acid addition salt orprodrug thereof for the manufacture of a pharmaceutical preparation forthe treatment of the above mentioned disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0042] Some of the compounds of general Formula I exist as opticalisomers thereof and such optical isomers are also embraced by theinvention.

[0043] Prodrugs of the compounds of general Formula I are also embracedby the invention.

[0044] The expression C₁₋₆-alk(en/yn)yl means that the group may be anC₁₋₆-alkyl, C₂₋₆-alkenyl, or C₂₋₆-alkynyl group.

[0045] The expression C₃₋₈-cycloalk(en)yl means a C₃₋₈-cycloalkyl group,or a C₃₋₈-cycloalkenyl group.

[0046] The term C₁₋₆ alkyl refers to a branched or unbranched alkylgroup having from one to six carbon atoms inclusive, such as methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and2-methyl-1-propyl.

[0047] Similarly, C₂₋₆ alkenyl and C₂₋₆ alkynyl, respectively, designatesuch groups having from two to six carbon atoms, inclusive. Preferredgroups are those having from two to four carbon atoms.

[0048] The terms C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylamino, C₁₋₆ alkylcarbonyl, etc. designate such groups in which thealkyl group is C₁₋₆ alkyl as defined above.

[0049] The term C₃₋₈ cycloalkyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms, such as cyclopropyl,cyclopentyl, cyclohexyl, etc.

[0050] The term C₃₋₈ cycloalkenyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms and containing a double bond.

[0051] The term aryl refers to a mono- or bicyclic carbocyclic aromaticgroup, such as phenyl, and naphthyl, in particular phenyl.

[0052] The term heteroaryl refers to a mono- or bicyclic heterocyclicaromatic group, such as indolyl, thienyl, pyrimidyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl,benzothienyl, pyridyl, and furanyl, in particular pyrimidyl, indolyl,and thienyl.

[0053] Halogen means fluoro, chloro, bromo or iodo.

[0054] As used herein the term acyl refers to a formyl, C₁₋₆alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C₁₋₆ alk(en/yn)ylcarbonyl,cycloalkylcarbonyl, or cycloalkyl-C₁₋₆ alk(en/yn)ylcarbonyl group andthe term thioacyl is the corresponding acyl group in which the carbonylgroup is replaced with a thiocarbonyl group.

[0055] The expression alk(en/yn)yl means that the group may be an alkyl,alkenyl, or alkynyl group.

[0056] As indicated in Formula I, the Y comprising ring may have avariable attachment point. Thus it may be linked to the W—(CH₂)_(n)group via the 1- or 2-position when Y is hydrocarbon or the 1-, 2- or3-position when Y is NR¹.

[0057] In Formula I, X is preferably —C═ or —CH— and Y is preferablyhydrocarbon or NR¹ wherein R¹ is hydrogen, C₁₋₆ alkyl, or C₁₋₆alkylcarbonyl. Most preferably Y is CH₂ and in that case the indane ringis preferably linked via the 1-position.

[0058] W is preferably a bond and n+m is preferably 1-4, in particular 1or 2.

[0059] R¹ is preferably hydrogen, methyl or acetyl most preferablyhydrogen.

[0060] Each of R²-R⁵ is preferably hydrogen, halogen, cyano or one ofthem a group NR¹³R¹⁴ wherein R¹³ is acyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or agroup R¹⁶R¹⁷NCO— wherein R¹⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,cycloalkyl- C₁₋₆ alkyl, aryl or heteroaryl and R¹⁷ is hydrogen or loweralkyl or R¹⁶ and R¹⁷ together with the N-atom to which they are linked,form a pyrrolidinyl, piperidinyl or perhydroazepin group. Morepreferably, R¹³ is formyl, acetyl, methylaminocarbonyl,methylaminothiocarbonyl, dimethylaminocarbonyl,dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl, cyclopropylcarbonyl, methyl, pyrrolidinylcarbonyl or4-fluorophenylaminocarbonyl and R¹⁴ is preferably hydrogen or loweralkyl, most preferably hydrogen or methyl, or R¹³ and R¹⁴ are linkedtogether to form a 5-7 membered unsubstituted lactam ring or apyrrolidinyl, piperidinyl or perhydroazepin.

[0061] R⁶ to R⁸ are preferably selected from hydrogen, halogen, cyano,nitro, C₁₋₆-alk(en/yn)yl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, or C₁₋₆alkylsulfonyl. More preferred R⁶ to R⁸ areselected from hydrogen, halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy.

[0062] A and B are preferably both O.

[0063] D is preferably methylene or methylene substituted with methyl,dimethyl formyl or acetyl.

[0064] A preferred subclass of compounds are those wherein Y is CH₂ theresulting indane ring being linked via the 2-position, A and B are bothO and D is optionally substituted methylene.

[0065] In another subclass of compounds Y is CH₂ the resulting indanering being linked via the 1-position, A and B are both O and D isoptionally substituted methylene.

[0066] In another subclass of compounds Y is NR¹ the dihydroindole ringbeing linked via the 3- or 1-position, preferably the 3-position, A andB are both O and D is optionally substituted methylene.

[0067] In a further subclass of compounds are those wherein W is a bond.

[0068] Another subclass of compounds of the invention are those whereinone of R²-R⁵ is a group —NR¹³R¹⁴.

[0069] In yet another subclass of compounds of the invention neither ofR²-R⁵ is a group —NR¹³R¹⁴.

[0070] In yet another subclass of compounds of the invention X is N.

[0071] In a last subgroup of compounds of the invention at least one ofA and B is S.

[0072] The acid addition salts of the invention are pharmaceuticallyacceptable salts of the compounds of Formula I formed with non-toxicacids. Exemplary of such organic salts are those with maleic, fumaric,benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, and theophylline aceticacids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitricacids.

[0073] The pharmaceutical compositions of this invention or those whichare manufactured in accordance with this invention may be administeredby any suitable route, for example orally in the form of tablets,capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and any pharmaceutically acceptablecarriers, diluents, excipients, or other additives normally used in theart may be used.

[0074] Conveniently, the compounds of the invention are administered inunit dosage form containing said compounds in an amount of about 0.01 to100 mg.

[0075] The total daily dose is usually in the range of about 0.05-500mg, and most preferably about 0.1 to 50 mg of the active compound of theinvention.

[0076] The compounds of the invention may be prepared as follows:

[0077] a) alkylating a piperazine, piperidine, or tetrahydropyridine ofthe formula II with an alkylating derivative of the formula III:

[0078]  wherein R²-R⁸, X, Y, A, B, D, n, m, W, and the dotted line areas previously defined, and L is a leaving group such as eg. halogen,mesylate, or tosylate; or

[0079] b) reducing the amide carbonyl in a compound of the followingFormula IV:

[0080]  wherein R²-R⁸, X, Y, A, B, D, m, W and the dotted line are aspreviously defined and n is 1, 2, 3, 4 or 5; or

[0081] c) introducing a substituent R^(2′), R^(3′), R^(4′) or R^(5′) byreacting a compound of the following Formula V:

[0082]  wherein one of R^(2′)-R^(5′) is hydrogen and the others are thecorresponding R², R³, R⁴, or R⁵ as previously defined and R⁶-R⁸, X, Y,A, B, D, m, n, W, and the dotted line are as previously defined, byusing a reactive reagent such as a halogen or a halogenating agent, asulfonating agent, a nitration agent or a reactive agent generatingcarbonium ions (RCO⁺, R⁺) wherein R is alkyl alkynyl, aryl cycloalkyl,heteroaryl cycloalkyl, or cycloalk(en/yn)yl; or

[0083] d) reducing the double bond in an indole compound of thefollowing Formula VI:

[0084]  wherein R¹, R²-R⁸, A, B, C, X, n, m and W are as previouslydefined; or

[0085] e) reducing the tetrahydropyridinyl double bond in derivatives ofthe following Formula VII:

[0086]  wherein R²-R⁸, Y, n, m, W, A, B and D are as previously defined;or

[0087] f) Reacting a dihydroindole derivative of formula VIII:

[0088]  wherein R²-R⁸, X, A, B, D, n, m, W, and the dotted line are aspreviously defined, with a reagent of the formula R¹-L, where L is aleaving group such as halogen, mesylate or tosylate and R¹ is aspreviously defined, or of the formula R^(1′)-hal or R^(1′)—OCOR, inwhich formulas hal is halogen, R^(1′) is acyl, thioacyl, a groupR¹⁵VCO—, or a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— where R¹⁵, V, R¹⁶ and R¹⁷are as previously defined except that neither R¹⁶ nor R¹⁷ may behydrogen, or with a lower alkylsulfonyl halogenide,trifluoromethylsulhonyl halogenide or an isocyanate or thioisocyanate ofthe formula R¹⁶—N═C═O or R¹⁶—N═C═S wherein R¹⁶ is as previously defined;

[0089] g) reacting an anilino derivative of the formula IX:

[0090]  wherein one of R²-R⁵ is NHR¹⁴, and R¹⁴ is defined as above andthe other R²-R⁸, X, Y, A, B, D, n, m, W, and the dotted line are aspreviously defined, with a reagent of the formula R¹³-L, where L is aleaving group such as halogen, mesylate or tosylate and R¹³ is aspreviously defined, or of the formula R^(13′)-hal or R^(13′)—OCOR, inwhich formulas hal is halogen, R^(13′) is acyl, thioacyl, a groupR¹⁵VCO—, or a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— where R¹⁵, V, R¹⁶ and R¹⁷are as previously defined except that neither R¹⁶ nor R¹⁷ may behydrogen, or with a lower alkylsulfonyl halogenide,trifluoromethylsulhonyl halogenide or an isocyanate or thioisocyanate ofthe formula R¹⁶—N═C═O or R¹⁶—N═C═S wherein R¹⁶ is as previously defined,

[0091] h) Alkylating a dihydroindole derivative of the Formula X with analkylating derivative of the Formula XI:

[0092] wherein R²-R⁸, X, Y, A, n, m, W, and the dotted line are aspreviously defined, and L is a leaving group such as eg. halogen,mesylate, or tosylate; or

[0093] i) reducing the carbonyl amide compounds of Formula XII:

[0094]  wherein R²-R⁸, X, Y, A, n, W and the dotted line are aspreviously defined and m is 1, 2, 3, 4 or 5; whereupon the compound ofFormula I is isolated as the free base or a pharmaceutically acceptableacid addition salt thereof.

[0095] The reaction in Methods f) and g) are conveniently performed atlow temperature (eg. below room temperature) in an inert solvent such asacetone, dichloromethane, tetrahydrofuran or dimethoxyethane whenreactive carboxylic acid chlorides, isocyanates, or isothiocyanates areused. Formylated amines are prepared from the corresponding amines byreaction in formic acid, with esters of formic acid, or by reaction withmixed formic acid anhydride prepared in situ. Generally reactiontemperatures are between 0° C. and the boiling point of the formylprecursor compounds.

[0096] The alkylations according to Methods a) and h) are generallyperformed by refluxing in a suitable solvent such as acetone, methylisobutyl ketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in thepresence of a base such as triethylamine or potassium carbonate.

[0097] The reductions of double bonds according to Methods d) and e) aregenerally performed by catalytic hydrogenation at low pressure (<3 atm.)in a Parr apparatus, or by using reducing agents such as diborane orhydroboric derivatives as produced in situ from NaBH₄ in trifluoroaceticacid in inert solvents such as tetrahydrofuran, dioxane, or diethylether.

[0098] The reductions according to Method b) and i) are generallyperformed by use of LiAlH₄, AlH₃ or diborane in an inert solvent such astetrahydrofuran, dioxane, or diethyl ether at room temperature or at aslightly elevated temperature.

[0099] The halogenation according to Method c) is generally performed byuse of chlorine, bromine, or N-chlorosuccinimide, N-bromosuccinimide oranother halogen precursor molecule, conveniently in the presence of acatalyst such as Fe ions or a mineral acid.

[0100] Methylene- or ethylenedioxyphenylpiperazine, piperidine andtetrahydropyridyl starting materials are commercially available or maybe prepared by literature procedures.

[0101] Key intermediates such as 1-indanecarboxylic acid ( V. Asham andW. H. Linnell, J. Chem. Soc. 1954, 4691-4693, Hansen et al. Helv. Chim.Acta 1982, 33, 325-343) and 6-nitro-1-indanecarboxylic acid (G. Kirschet al. Just. Lieb. Ann. Chem. 1976, 10, 1914) were prepared according towell-known literature procedures.

EXPERIMENTAL SECTION

[0102] Melting points were determined on a Büchi SMP-20 apparatus andare uncorrected. Mass spectra were obtained on a Quattro MS-MS systemfrom VG Biotech, Fisons Instruments. The MS-MS system was connected toan HP 1050 modular HPLC system. A volume of 20-50 μl of the sample (10μg/ml) dissolved in a mixture of 1% acetic acid in acetonitril/water 1:1was introduced via the autosampler at a flow of 30 μl/min into theElectrospray Source. Spectra were obtained at two standard sets ofoperating conditions. One set to obtain molecular weight information(MH+) (21 eV) and the other set to induce fragmentation patterns (70eV). The background was subtracted. The relative intensities of the ionsare obtained from the fragmentation pattern. When no intensity isindicated for the Molecular Ion (MH+) this ion was only present underthe first set of operating conditions. 1H NMR spectra were recorded ofall novel compounds at 250 MHz on a Bruker AC 250. Deuterated chloroform(99.8% D) or dimethylsulfoxide (99.9% D) were used as solvents. TMS wasused as internal reference standard. Chemical shift values are expressedin ppm-values. The following abbreviations are used for multiplicity ofNMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet,h=heptet, dd=double doublet, dt=double triplet, dq=double quartet,tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidicprotons are generally omitted. Content of water in crystalline compoundswas determined by Karl Fischer titration. Standard workup proceduresrefer to extraction with the indicated organic solvent from properaqueous solutions, drying of combined organic extracts (anhydrous MgSO₄or Na₂SO₄), filtering and evaporation of the solvent in vacuo. Forcolumn chromatography silica gel of type Kieselgel 60, 230-400 mesh ASTMwas used.

EXAMPLE 1 1-Indanylmethanol, 1a

[0103] To a suspension of LiAlH₄ (4.7 g) in diethyl ether (200 ml) wasadded dropwise a solution of AlCl₃ in diethyl ether (200 ml). A solutionof 1-indanecarboxylic acid (10 g) (prepared according to the method ofHansen et al. Helv. Chim. Acta 1982, 33, 325-343) in dry tetrahydrofuran(200 ml) was added dropwise at 10-15° C. The mixture was finally stirredat room temperature for 1.5 hours. Excess AlH₃ was destroyed by additionof concentrated aqueous NaOH solution (25 ml) at 0° C. Precipitatedinorganic salts were filtered off and the solvents evaporated in vacuoleaving 6.8 g of the title compound 1a as a viscous oil which was usedwithout further purification.

[0104] The following 1-indanylmethanols were prepared in a similarmanner:

[0105] 6-Bromo-1-indanylmethanol from alane reduction of thecorresponding methyl 6-bromo-1-indanecarboxylic acid ester, isolated asa viscous oil. 1b.

EXAMPLE 2 6-Cyano-1-indanylmethanol 2a

[0106] To a solution of 6-bromo-1-indanylmethanol (20 g) inN-methyl-2-pyrrolidone (NMP) (380 ml) was added CuCN (79 g). The mixturewas heated at 160° C. for 6 hours. After cooling to 80-90° C. themixture was poured into an aqueous solution (500 ml) of NaCN (4g). Afterstirring for 20 minutes excess CuCN was filtered off. Ethyl acetate (300ml) was added and the organic phase was separated and worked-up. Theremaining oil was dissolved in diethyl ether (300 ml) and washed withsaturated brine (2×100 ml). The organic phase was separated and workedup according to the general procedure leaving 14.6 g of crude titlecompound 2a as a visceous oil. Column chromatography on silica gel(eluent:ethylacetat/heptane 6:4) afforded pure 2a (8.7 g) which was usedwithout further purification.

EXAMPLE 3 6-Cyano-1-indanylmethanol methanesulfonate, 3a

[0107] To a solution of 6-cyano-1-indanylmethanol 2a (3 g) andtriethylamine (2.8 ml) in dichloromethane (50 ml) was added dropwise asolution of methansulfonylchloride (1.5 ml) in dichloromethane (25 ml)at 0° C. The mixture was stirred at room temperature for 1 hour. Waterwas added (200 ml) and the organic phase was subsequently separated andworked-up according to the standard procedure above. The remainingcrystalline product was stirred with diethyl ether and filtered off.Yield 2.7 g. Mp 62-63° C.

[0108] The following methanesulfonates were prepared in a similarmanner:

[0109] 1-Indanylmethanol methanesulfonate, 3b. Isolated as a viscous oil6-Bromo-1-indanylmethanol methanesulfonate, 3c.

EXAMPLE 4 (Method a)1-(1-Indanylmethyl-4-(3,4-methylenedioxyphenyl)piperazine, fumarate, 4a

[0110] A mixture of 1-Indanylmethanol methanesulfonate, 3b (5.8 g) and1-(3,4-methylene-dioxyphenyl)piperazine (commercially available) (11 g)in NMP (100 ml) was heated at 110° C. for 5 hours. After cooling to roomtemperature the mixture was poured into diluted aqueous NH₄OH.Extraction with a 1:1 mixture of diethyl ether/ethyl acetate (3×100 ml)afforded 13.1 g of a very impure product. Purification by columnchromatography on silica gel (eluted with heptane/ethylacetate/triethylamine 80/20/4) yielded pure title compound (2.7) whichprecipitated as the fumarate salt 4a from ethanol. Mp>311° C. ¹H NMR(DMSO-d₆): d 1.70-1.90 (m, 1H); 2.15-2.30 (m, 1H); 2.45 (dd, 1H); 2.65(broad t, 4H); 2.55-2.70 (m, 2H); 2.70-2.95 (m, 2H); 3.05 (broad t, 4H);3.35 (quin, 1H); 5.85 (s, 2H); 6.45 (dd, 1H); 6.65 (s, 2H); 6.70 (d,1H); 6.75 (d, 1H); 7.15-7.30 (m, 3H); 7.35 (dd, 1H). MS m/z (%): 337(MH+, 62%), 207 (24%), 131 (100%).

[0111] In a similar way the following compound was prepared:

1-(6-Bromo-1-indanylmethyl-4-(3,4-methylenedioxyphenyl)piperazine,fumarate, 4b mp 158-161° C.

[0112]¹H NMR (DMSO-d₆): d 1.65-1.80 (m, 1H); 2.10-2.25 (m, 1H); 2.40(dd, 1H); 2.60 (broad t, 4H); 2.50-2.60 (m, 2H); 2.65-2.90 (m, 2H); 3.05(broad t, 4H); 3.40 (quin, 1H); 5.95 (s, 2H); 6.35 (dd, 1H); 6.65 (s,2H); 6.70 (d, 1H); 6.75 (d, 1H); 7.15 (d, 1H); 7.25 (dd, 1H); 7.55 (d,1H). MS m/z (%): 417 (35%), 415 (MH+, 35%), 219 (30%), 209 (32%), 206(30%), 164 (24%), 130 (100%).

EXAMPLE 51-[2-[4-(3,4-methylenedioxyphenyl)-piperazine-1-yl]methylcarbonyl]-indane,5a

[0113] A solution of indane-1-acetic acid (Anderson, A. G. et al; J.Org. Chem. 1973, 38(8), 1439-1444) (2.5 g, 14.2 mmol), DMF (1 ml) andSOCl₂ (6.2 g, 52.5 mmol) in CH₂Cl₂ (100 ml) was refluxed for 4 h. Themixture was evaporated and re-evaporated from toluene to give thecorresponding acid chloride. To a solution of1-(3,4-methylenedioxyphenyl)-piperazine hydrochloride (6.9 g, 28.4 mmol)and TEA (6 ml) in THF (70 ml) was added dropwise over 20 min. a solutionof the acid chloride in THF (70 ml). The mixture was stirred for 1 h andevaporated. H₂O (30 ml) was added to the remanence and the mixture wasextracted with CH₂Cl₂ (2×100 ml). After washing with H₂O (10 ml) andbrine (10 ml) the combined organic phases were dried with MgSO₄ andevaporated. The product was purified by column chromatography(EtOAc:heptane=1:1) to give the title compound 5a (3.3 g, 64%): ¹H NMR(DMSO-d₆) d 1.65-1.82 (1H, m), 2.34-2.54 (2H, m), 2.72-2.83 (1H, dd),2.86-3.07 (6H, m), 3.48-3.59 (2H, m), 3.62-3.76 (1H, m), 3.77-3.82 (2H,m), 5.88 (2H, s), 6.32 (1H, dd), 6.53 (1H, d), 6.70 (1H, d), 7.11-7.25(4H, m).

[0114] The following amide was prepared in a similar manner:

2-[4-(3,4-methylenedioxyphenyl)-piperazine-1-yl]carbonyl]-indane, 5b.,mp 114-116° C.

[0115] This compound was prepared from indane-2-carboxylic acid whichagain was prepared by heating a solution of indane-2,2-dicarboxylic acid(17 g, Baeyer and Perkin, Ber. 1884, 17, 122) in NMP (200 ml) to 150° C.for 1 hour. After cooling to 20° C. the solution was poured in water(300 ml) and concentrated hydrochloric acid was added to pH=1.Conventional work up with ether gave indane-2-carboxylic (4.7 g). Mp132-33° C. (from ether).

EXAMPLE 61-[2-[4-(3,4-methylenedioxyphenyl)-piperazine-1-yl]ethyl]-indanefumarate, 6a

[0116] To a supension of LiAlH₄ (1.0 g, 27.2 mmol) in THF (70 ml) wasadded dropwise over 20 min. a solution of 5a (3.3 g, 9.1 mmol) in THF(70 ml). The mixture was refluxed for 1.5 h and then cooled to 10-15° C.After dropwise addition of H₂O (1 ml), aqueous (15%) NaOH (1 ml) and H₂O(5 ml), the solution was filtered and evaporated to allmost dryness. Theremanence was dissolved in CH₂Cl₂ and after drying with MgSO₄, thesolution was evaporated to give the free base of 6a, which was dissolvedin acetone (15 ml) and treated with fumaric acid (1.1 g) dissolved inEtOH to give the title compound 6a (2.5 g, 59%): mp 191-192° C., ¹H NMR(DMSO-d₆) d 1.45-1.70 (2H, m), 2.00-2.15 (1H, m), 2.15-2.30 (1H, m),2.50-2.60 (2H, m), 2.65-2.70 (4H, m), 2.70-2.90 (2H, m), 3.00-3.20 (5H,m), 5.90 (1H, s), 6.30 (2H, dd), 6.60 (2H, s), 6.65 (1H, d), 6.70 (1H,d), 7.10-7.30 (4H, m). MS m/z (%): 351 (MH+, 100%), 188 (27%), 117(19%).

[0117] The following compound was prepared in a similar way usingcompound 5b as starting material:

2-[4-(3,4-methylenedioxyphenyl)-piperazine-1-yl]methyl]-indane, oxalate,6b, mp 197-199° C.

[0118] hu 1H NMR (DMSO-d₆) d 2.70 (dd, 2H), 2.85 (quintet, 1H),2.95-3.35 (m, 12H), 5.95 (s, 2H), 6.40 (dd, 1H), 6.75 (d, 1H), 6.80 (d,1H), 7.10-7.25 (m, 4H). MS m/z (%): 337 (MH+, 100%), 174, (14%),131(26%).

EXAMPLE 71-Acetyl-2,3-dihydro-3-[1-(2-methanesulphonyl)ethyl]-1H-indole, 7a

[0119] To a solution of indole-3-acetic acid (100 g) in methanol (1 l)was added ether saturated with HCl (200 ml), and the solution was leftat room temperature for 3 hours. The solution as evaporated in vacuo,and the residue was dissolved in THF 1.2 l) and added slowly withcooling to a stirred suspension of LiAlH₄ (28.6 g) in THF (1 l). Afterstirring for 2 hours at room temperature, the mixture was cooled in anice bath, and water (57 ml), 15% NaOH (29 ml), and water (143 ml) wasadded. The mixture was filtered and evaporated in vacuo, and the residue(84.9 g) was dissolved in dioxane (1.5 l). Borane trimethylamine complex(200 g) was added, and and to the stirred mixture was added concentratedhydrochloric acid (150 ml) during 1 hour. The mixture was heated to 40°C. for 30 minutes and then to reflux for 2.5 hours. Then 6 Mhydrochloric acid (460 ml) was added and reflux was continued for 30minutes. The solution was concentrated in vacuo, and the residue waspoured on ice. The solution was washed with ether and was made basicwith concentrated NaOH and then extracted with ether. The organic phasewas dried over MgSO₄ and was evaporated in vacuo. The residue wasdissolved in CH₂Cl₂ (680 ml) and triethylamine (68 ml). Acetyl chloride(36 ml) was added at 5° C. during 1 hour. After further stirring for 1hour at room temperature, the mixture was washed with dilutehydrochloric acid, and NaHCO₃ solution. After drying over MgSO₄ andevaporation in vacuo, the residue was dissolved in methanol (500 ml),and 30% Na-methanolat (10 ml) was added. The mixture was stirred for 4hours at room temperature and was then evaporated in vacuo and wasdissolved in CH₂Cl₂ and was washed with saturated NaCl solution, driedover MgSO₄ and evaporation in vacuo. The residue (75.4 g) was dissolvedin CH₂Cl₂ (1 l) and triethylamine (100 ml). With cooling was added asolution of methanesulphonic chloride (27 ml) in CH₂Cl₂ (175 ml) at 10°C. After stirring for 30 minutes at 0° C. and 1 hour at roomtemperature, the mixture was evaporated in vacuo and was purified onsilica gel eluted with ethyl acetate to give the title produduct as anoil (74 g).

EXAMPLE 8 1-(4-Chloro-1-oxobtutan-1-yl)-2,3-dihydro-1H-indole, 8a

[0120] The title compound was prepared in a similar way as Example 7using a cooled solution of 2,3-dihydro-1H-indole (10 g) in CH₂Cl₂ (125ml) and triethylamine (13 ml) by adding 4-chlorobutyryl chloride (10 ml)at less than 10° C. Conventional work up gave the title compound as anoil. Yield 16.4 g.

EXAMPLE 92,3-Dihydro-3-[4-[4-[(3,4-methylenedioxyphenyl)piperazine-1-yl]butyl-1-oxo]]-1H-indole,oxalate 9a

[0121] A mixture of 3,4-methylenedioxyphenylpiperazine (2.50 g), 8a(2.78 g), and K₂CO₃ (1.85 g) in MIBK (100 ml) was heated to reflux for16 hours. The mixture was filtrated and evaporated in vacuo, and theresidue was dissolved in ethyl acetate and worked up in a conventionalmanner to give a crude product (3.5 g) which was purified on silica geleluted with ethyl acetate-heptane triethylamine (64:31:5). The titleoxalate was crystallized from acetone. Yield 0.20 g, mp 198-200° C. ¹HNMR (DMSO-d₆) d 1.85-2.00 (m, 2H), 2.55 (t, 2H), 3.00 (t, 2H), 3.05-3.30(m, 8H), 3.50-4.00 (m, 2H), 4.05 (t, 1H), 5.95 (s, 2H), 6.40 (dd, 1H),6.75 (d, 1H), 6.80,(d, 1H), 7.00 (t, 1H), 7.15 (t, 1H), 7.25 (d, 1H),8.10 (d, 1H).

1-Acetyl-2,3-dihydro-3-[2-[4-[(3,4-methylenedioxyphenyl)piperazine-1-yl]ethyl]]1H-indole,9b

[0122] From 7a and 3,4-methylenedioxyphenylpiperazine. Mp 185-7° C. 1HNMR (DMSO-d6) d 1.75-2.00 (m, 1H), 2.10-2.25 (m, 1H), 2.15 (s, 3H),2.90-3.15 (m, 2H), 3.2 (d, 8H), 3.35-3.55 (m, 1H), 3.80 (dd, 1H), 4.20(t, 1H), 5.90 (s, 2H), 6.35 (dd, 1H), 6.75 (d, 1H), 6.80 (d, 1H), 7.00(t, 1H), 7.20 (t, 1H), 7.30 (d, 1H), 8.05 (d, 1H). MS m/z (%): 394 (MH+,100%), 219 (3%), 146 (2%).

PHARMACOLOGICAL TESTING

[0123] The compounds of the invention were tested in well recognized andreliable methods. The tests were as follows:

³H-YM-09151-2 Binding

[0124] By this method the inhibition by drugs of the binding of thedopamine D₄ antagonist ³H-YM-09151-2 to dopamine D₄ receptors in clonedhuman dopamine receptor subtype 4.2 membranes is determined in vitro.Accordingly, this is a test for affinity for dopamine D₄ receptors. Thetest is performed using a preparation of cloned dopamine D₄ cellmembranes CRM-016®, Dupharma A/S, Denmark, in accordance with theproduct specifications. The results are given in the following Table 1as IC₅₀-values. TABLE 1 Binding Data (IC₅₀ values in nM or % inhibitionof binding at 50 nM) Comp. No. Binding 4a 8.8 4b 33% at 50 nM 6a 5.6 6b1.8 9a 4.3 9b 3.7

³H-8-OH-DPAT Binding

[0125] By this method the inhibition by drugs of the binding of the5-HT_(1A) agonist ³H-8-OH-DPAT (1 nM) to 5-HT_(1A) receptors inmembranes from rat brain minus cerebellum is determined in vitro.Accordingly, this is a test for affinity for 5-HT_(1A) receptor. Thetest is performed as described by Hyttel et al., Drug. Dev. Res., 1988,15, 389-404.

³H-Ketanserin Binding

[0126] By this method the inhibition by drugs of the binding of³H-Ketanserin (0,5 nM) to 5-HT_(2A) receptors in membranes from rat isdetermined in vitro. The method is described in Hyttel, Pharmacology &Toxicology, 61, 126-129, 1987.

[0127] In addition to the above tests, the compounds of the inventionwere tested with respect to affinity for the dopamine D₂ receptor bydetermining their ability to inhibit the binding of ³H-spiroperidol toD₂ receptors by the method of Hyttel et al, J. Neurochem., 1985, 44,1615. Furthermore, they were tested with respect to their 5-HT reuptakeinhibiting effect by measuring their ability to inhibit the uptake of³H-serotonin in rat brain synapsomes in vitro by the method descibed byHyttel and Larsen, Acta Pharmacol. Tox., 1985, 56, suppl. 1, 146-153.

[0128] In general, the compounds of the invention have been foundpotently to inhibit the binding of tritiated YM-09151-2 to dopamine D₄receptors. Furthermore, many of the compounds have been found to inhibitthe binding of tritiated 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)to 5-HT_(1A) receptors and/or the binding of ³H ketanserin to 5-HT_(2A)receptors in vitro. Some compounds only bind to one of the two serotoninreceptor subtypes, 5-HT_(1A) or 5-HT_(2A). In addition to these affects,a number of the compounds have proven to have the further advantage of apotent 5-HT reuptake inhibiting effect and/or effects at otherserotonergic receptors. The compounds have no substantial or only weakaffinity for the dopamine D₂ receptor.

[0129] Accordingly, the compounds of the invention are considered usefulin the treatment of positive and negative symptoms of schizophrenia,other psychoses, anxiety disorders, such as generalised anxietydisorder, panic disorder, and obsessive compulsive disorder, depression,alcohol abuse, impulse control disorders aggression, side effectsinduced by conventional antipsychotic agents, ischaemic disease states,migraine, senile dementia and cardiovascular disorders and in theimprovement of sleep.

FORMULATION EXAMPLES

[0130] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art.

[0131] For example: Tablets may be prepared by mixing the activeingredient with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a conventional tabletting machine. Examplesof adjuvants or diluents comprise: corn starch, potato starch, talcum,magnesium stearate, gelatine, lactose, gums, and the like. Any otheradjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients.

[0132] Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilisation of the solution and filling in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

[0133] Typical examples of recipes for the formulation of the inventionare as follows: 1) Tablets containing 5.0 mg of Compound 4a calculatedas the free base: Compound 4a 5.0 mg Lactose 60 mg Maize starch 30 mgHydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mgCroscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg Tabletscontaining 0.5 mg of Compound 6a calculated as the free base: Compound6a 0.5 mg Lactose 46.9 mg Maize starch 23.5 mg Povidone 1.8 mgMicrocrystalline cellulose 14.4 mg Croscarmellose Sodium Type A 1.8 mgMagnesium stearate 0.63 mg Syrup containing per millilitre: Compound 9b25 mg Sorbitol 500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mgMethyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 ml Flavour 0.05mg Saccharin natrium 0.5 mg Water ad 1 ml Solution for injectioncontaining per millilitre: Compound 4a 0.5 mg Sorbitol 5.1 mg AceticAcid 0.05 mg Saccharin sodium 0.5 mg Water ad 1 ml

1. An indane or dihydroindole compound of formula I

wherein A and B are independently O or S; D is a methylene groupoptionally substituted with one or two C₁₋₄ alkyl groups; Y is ahydrocarbon group completing an indane ring, a group NR¹ completing adihydroindole ring, or a group N completing a dihydroindole ringattached via the 1-position; W is a bond, and n+m is 1, 2, 3, 4, 5, or6; W is CO, SO, or SO₂, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3,provided that n+m is not more than 6; or W is O, S, n is 2, 3, 4, or 5and m is 0, 1, 2, or 3, provided that n+m is not more than 6, andprovided that when Y is N completing a dihydroindole ring attached viathe 1-position then m is 2, or 3; and when Y is NR¹ completing adihydroindole ring linked via the 2-position then m is 1, 2, or 3; thedotted line, emanating from X, indicates an optional bond; when it doesnot indicate a bond X is N, CH or COH; and when it indicates a bond X isC; R¹ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl, aryl,heteroaryl, aryl- C₁₋₆ alkyl, heteroaryl-C₁₋₆ alkyl, acyl, thioacyl,C₁₋₆ alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl orheteroarylsulfonyl, or R¹⁵VCO— wherein V is O or S and R¹⁵ is C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl,or a group R¹⁶R¹⁷NCO— or R¹⁶R¹⁷NCS— wherein R¹⁶ and R¹⁷ areindependently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆ alkyl, aryl or heteroaryl, or R¹⁶ and R¹⁷ together withthe N-atom to which they are linked, form a pyrrolidinyl, piperidinyl orperhydroazepin group; R²-R⁵ are independently selected from hydrogen,halogen, cyano, nitro, C₁₋₆ alk(en/yn)yl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,hydroxy, C₃₋₈ cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆ alk(en/yn)yl,C₁₋₆ alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl,trifluoromethyl, trifluoromethylsulfonyloxy and C₁₋₆ alkylsulfonyl, oneof R²-R⁵ alternatively being a group —NR¹³R¹⁴ wherein R¹³ is selectedfrom the R¹ substituents; R¹⁴ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalk(en)yl, C₃₋₈ cycloalk(en)yl-C₁₋₆alk(en/yn)yl, aryl, heteroaryl, aryl-C₁₋₆ alkyl or heteroaryl-C₁₋₆alkyl, or R¹³ and R¹⁴ together with the N-atom to which they are linkedform a group

 wherein Q is C═O, C═S or CH₂; T is NH, S, O or CH₂; and p is 1-4,inclusive; or two adjacent groups taken from R²-R⁵ may be joined anddesignate a —(CH₂)₃— or —CH═CH—NH— thereby forming a fused 5-memberedring; R⁶-R⁸ are independently hydrogen, halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, or C₁₋₆ alkylsulfonyl; with the proviso that thesubstituent R³ or R⁴ in 6-position may not be —NR¹³R¹⁴ when Y is CH₂ andthe ring is linked via the 1-position; or a pharmaceutically acceptableacid addition salt thereof.
 2. A compound of claim 1 , characterized inthat Y is CH₂ and that the resulting indane ring is linked to theW—(CH₂)_(n) group via the 1- or 2-position, preferably the 1-position.3. A compound of claim 1 , characterized in that Y is NR¹ and that theresulting dihydroindole ring is linked to the W—(CH₂)_(n) group via the1- or 3-position.
 4. A compound of claim 3 , characterized in that R¹ ishydrogen, C₁₋₆ alkyl, or C₁₋₆ alkylcarbonyl.
 5. A compound of claims 1,2, 3 or 4, characterized in that A and B are both O.
 6. A compound ofclaims 1, 2, 3, 4 or 5, characterized in that D is methylene ormethylene substituted with one or two methyl groups.
 7. A compound ofany of claims 1-6, characterized in that W is a bond and n+m is 1, 2, 3or
 4. 8. A compound of claim 7 , characterized in that n+m is 1 or
 2. 9.A compound of any of claims 1-8, characterized in that none of R²-R⁵ isa group NR¹³R¹⁴.
 10. A compound of claim 9 , characterized in that eachof R²-R⁵ is selected from the group consisting of hydrogen, halogen orcyano.
 11. A compound of any of claims 1-8, characterized in that atleast one of R²-R⁵ is a group NR¹³R¹⁴.
 12. A compound of claim 11 ,characterized in that R¹³ is acyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or a groupR¹⁶R¹⁷NCO— wherein R¹⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,cycloalkyl- C₁₋₆ alkyl, aryl or heteroaryl and R¹⁷ is hydrogen or C₁₋₆alkyl or R¹⁶ and R¹⁷ together with the N-atom to which they are linked,form a pyrrolidinyl, piperidinyl or perhydroazepin group and R¹⁴hydrogen or lower alkyl, preferably hydrogen or methyl.
 13. A compoundof claim 12 , characterized in that R¹³ is formyl, acetyl,methylaminocarbonyl, methylaminothiocarbonyl, dimethylaminocarbonyl,dimethylaminothiocarbonyl, methylsulfonyl, aminocarbonyl,cyclopropylcarbonyl, methyl, pyrrolidinylcarbonyl or4-fluorophenylaminocarbonyl.
 14. A compound of claim 11 , characterizedin that R¹³ and R¹⁴ are linked together to form a 5-7 memberedunsubstituted lactam ring or a pyrrolidinyl, piperidinyl orperhydroazepin.
 15. A compound of claim 2 , characterized in thatwherein Y is CH₂ the resulting indane ring being linked via the2-position, A and B are both O and D is optionally substitutedmethylene.
 16. A compound of claim 2 , characterized in that Y is CH₂the resulting indane ring being linked via the 1-position, A and B areboth O and D is optionally substituted methylene.
 17. A compound ofclaim 3 , characterized in that Y is NR¹ the dihydroindole ring beinglinked via the 3- or 1-position, preferably the 3-position, A and B areboth O, D is optionally substituted methylene.
 18. A compound of any ofclaims 15-17, characterized in that W is a bond.
 19. A compound of anyof claims 15-18, characterized in that n+m is 1 or 2, and R¹-R⁵ are allhydrogen.
 20. A compound of any of claims 15-19, characterized in that Xis N.
 21. A compound of claim 1 , characterized in that it is selectedfrom the following compounds:1-(1-Indanylmethyl)-4-(3,4-methylendioxyphenyl)piperazine,1-(6-Bromo-1-indanylmethyl-4-(3,4-methylendioxyphenyl)piperazine,1-[2-[4-(3,4-methylenedioxyphenyl)-piperazine-1-yl]ethyl]-indane,2,3-Dihydro-3-[4-[4-[(3,4-methylendioxyphenyl)piperazine-1-yl]butyl-1-oxo]]-1H-indole,1-Acetyl-2,3-dihydro-3-[2-[4-[(3,4-methylendioxyphenyl)piperazine-1-yl]ethyl]]-1H-indoleor 1-(2-Indanylmethyl)-4-(3,4-methylendioxyphenyl)piperazine.
 22. Use ofa compound of any of claims 1-21 for the manufacture of a medicamentuseful in the treatment of positive and negative symptoms ofschizophrenia, other psychoses, anxiety disorders, such as generalisedanxiety disorder, panic disorder, and obsessive compulsive disorder,depression, alcohol abuse, impulse control disorders, aggression, sideeffects induced by conventional antipsychotic agents, ischaemic diseasestates, migraine, senile dementia and cardiovascular disorders and inthe improvement of sleep.
 23. Pharmaceutical composition characterizedin that it comprises a compound of any of claims 1-21 in atherapeutically effective amount together with one or morepharmaceutically acceptable carriers or diluents.